Metabolic/inflammatory/vascular comorbidity in psychiatric disorders; soluble epoxide hydrolase (sEH) as a possible new target.

The common and severe psychiatric disorders, including major depressive disorder (MDD) and bipolar disorder (BD), are associated with inflammation, oxidative stress and changes in peripheral and brain lipid metabolism. Those pathways are implicated in the premature development of vascular and metabolic comorbidities, which account for considerable morbidity and mortality, including increased dementia risk. During endoplasmic reticulum stress, the soluble epoxide hydrolase (sEH) enzyme converts anti-inflammatory fatty acid epoxides generated by cytochrome p450 enzymes into their corresponding and generally less anti-inflammatory, or even pro-inflammatory, diols, slowing the resolution of inflammation. The sEH enzyme and its oxylipin products are elevated post-mortem in MDD, BD and schizophrenia. Preliminary clinical data suggest that oxylipins increase with symptoms in seasonal MDD and anorexia nervosa, requiring confirmation in larger studies and other cohorts. In rats, a soluble sEH inhibitor mitigated the development of depressive-like behaviors. We discuss sEH inhibitors under development for cardiovascular diseases, post-ischemic brain injury, neuropathic pain and diabetes, suggesting new possibilities to address the mood and cognitive symptoms of psychiatric disorders, and their most common comorbidities.

A placebo-controlled comparison of lithium and triiodothyronine augmentation of tricyclic antidepressants in unipolar refractory depression.

OBJECTIVE: To directly compare the efficacy of lithium carbonate and liothyronine sodium (triiodothyronine) in the augmentation of therapeutic response in antidepressant nonresponders. DESIGN: A randomized, double-blind, placebo-controlled study of 2 weeks' duration. SETTING: The Mood Disorders Program, Clarke Institute of Psychiatry and the University of Toronto, Ontario. PATIENTS: Fifty outpatients, males and females, with unipolar, nonpsychotic major depression who had failed to respond to treatment with desipramine hydrochloride or imipramine hydrochloride. RESULTS: Both liothyronine and lithium were more effective than placebo in reducing scores on the Hamilton Rating Scale for Depression. However, the antidepressant augmenting effect of these two compounds did not differ from each other. When response was defined as a 50% or more reduction in the Hamilton Rating Scale for Depression scores and a final score less than 10, we found that 10 of 17 subjects responded to liothyronine, nine of 17 responded to lithium and three of 16 responded to placebo. CONCLUSIONS: Our study suggests that both lithium and liothyronine may be considered as alternatives in augmenting antidepressant response in patients who do not respond to treatment with a tricyclic antidepressant.

Hormonal and subjective responses to intravenous meta-chlorophenylpiperazine in bulimia nervosa.

BACKGROUND: Several lines of evidence point to serotonergic abnormalities in patients with bulimia nervosa (BN). Our goal was to further examine central serotonergic function in bulimic patients using neuroendocrine and subjective responses to the postsynaptic serotonin receptor agonist meta-chlorophenylpiperazine (mCPP). METHOD: Using a double-blind, randomized, placebo-controlled design, we assessed neuroendocrine and subjective responses to intravenous mCPP (0.1 mg/kg) and placebo in 16 patients with BN, free of medication, and 14 normal control subjects. Plasma prolactin and cortisol levels were used as neuroendocrine measures, whereas subjective responses were measured using a visual analog scale of 10 different mood states. RESULTS: Compared with controls, the BN group exhibited blunted prolactin and net cortisol responses following mCPP challenge. Subjective responses, while preliminary, also differed between groups on items related to anxiety, calmness, and altered self-awareness. CONCLUSION: Evidence of dysfunction at or downstream of central serotonergic receptors in BN confirms and extends findings of prior research.

Hormonal and subjective responses to intravenous m-chlorophenylpiperazine in women with seasonal affective disorder.

BACKGROUND: There is emerging evidence of serotonergic dysfunction in patients with seasonal affective disorder (SAD). We examined central serotonergic function in female patients with SAD (fall-winter pattern) by means of neuroendocrine and subjective responses to the postsynaptic serotonin receptor agonist m-chlorophenylpiperazine. METHODS: Using a double-blind, randomized, placebo-controlled design, we assessed neuroendocrine and subjective responses to m-chlorophenylpiperazine (0.1 mg/kg intravenously) and placebo in 14 unmedicated female patients with SAD in the depressed state and 15 female normal controls. All testing was done in the fall-winter months and during the follicular phase of the menstrual cycle. Plasma prolactin and cortisol levels were used as neuroendocrine measures, while subjective responses were assessed by means of visual analog scales of 10 mood states. RESULTS: On the basis of net responses to m-chlorophenylpiperazine (placebo effects subtracted from drug effects), patients with SAD exhibited blunted prolactin responses and less sadness than normal controls in response to the drug. When order of presentation of drug and placebo was taken into consideration, altered "calm" and "high" responses were also found in the patient group. CONCLUSION: Evidence of dysfunction at or downstream to central serotonergic receptors in female patients with SAD confirms and extends findings from previous research.

Folate, B12, and life course of depressive illness.

Forty-four consecutive, unmedicated outpatients with a major depressive disorder were evaluated to determine the relationships in life course, severity of depressive illness, and serum folate and B12 levels. Duration of current episode was significantly inversely correlated with folate levels. Age at onset of illness was significantly correlated with B12. In a subgroup of recurrent depressives, current age and age at onset of depressive illness were positively correlated with folate. The findings are discussed in light of the current hypotheses regarding the association of folate and mood.

The Tridimensional Personality Questionnaire in major depression.

The authors examined Tridimensional Personality Questionnaire scores in 40 patients with unipolar nonpsychotic major depression before and after antidepressant treatment. They found that scores on the novelty seeking and reward dependence dimensions were not affected by depressed state or by treatment response status. However, scores on the harm avoidance dimension were significantly lower in antidepressant responders and were altered by depressed state.

Side effects of light therapy in seasonal affective disorder.

The authors report the frequency of side effects of light therapy in 105 patients with seasonal affective disorder treated with three intensities of light. Common symptoms to emerge during treatment were headache (19%), eyestrain (17%), and feeling "wired" (14%). There was no relationship between side effects and intensity of light used.

Multicenter, placebo-controlled study of fluoxetine in seasonal affective disorder.

OBJECTIVE: The authors investigated the efficacy and safety of fluoxetine in the treatment of winter seasonal affective disorder. METHOD: Sixty-eight outpatients who met the DSM-III-R criteria for recurrent major depressive episodes, seasonal (winter) pattern, were randomly assigned to 5 weeks of treatment with fluoxetine, 20 mg/day (N = 36), or placebo (N = 32). The outcome measures included the 29-item modified Hamilton Depression Rating Scale, administered by experienced clinicians, and the self-rated Beck Depression Inventory; adverse events and safety data were also recorded. Clinical response was defined as a greater than 50% reduction in depression score between baseline and study termination. RESULTS: Both groups showed significant improvement. The fluoxetine group had lower depression scores at termination than the placebo group, but these differences did not achieve statistical significance. However, the rate of clinical response in the fluoxetine group (59%) was superior to that in the placebo group (34%). Post hoc analyses showed that the greatest fluoxetine responses were in the most markedly depressed patients and that overall response was greater for patients studied later in the season. Fluoxetine was well tolerated, and few subjects dropped out because of adverse events. CONCLUSIONS: On the basis of clinical response rate, fluoxetine appears to be an effective, well-tolerated treatment for seasonal affective disorder. Because the differences between fluoxetine and placebo in the continuous outcome measures did not reach statistical significance, further studies with larger study groups and longer treatment periods are required to conclusively demonstrate efficacy of fluoxetine for seasonal affective disorder.

Major depression and subclinical (grade 2) hypothyroidism.

Subclinical hypothyroidism (SCH) has been reported to occur in patients with a variety of affective syndromes. However, the clinical correlates of SCH in patients with major depression have received limited attention. We therefore examined demographic, clinical and treatment response variables in a cohort of patients with unipolar, nonpsychotic major depression with and without SCH. Of 139 subjects, 19 had SCH defined as an elevated basal TSH with normal circulating levels of T3 and T4. Major depression with SCH differed from that without SCH by the presence of a concurrent panic disorder and a poorer antidepressant response.

Bright light augmentation in antidepressant nonresponders.

BACKGROUND: This study was designed to examine the potential benefit of the addition of bright lights to antidepressant treatment in depressed subjects. METHOD: Ten patients who presented during the winter months with major depression and who had failed an adequate trial of antidepressants or who had relapsed following a successful course of antidepressants underwent a 2-week course of bright light therapy. RESULTS: Augmentation with bright lights resulted in substantial improvement in 7 of the 10 patients. CONCLUSION: Bright light augmentation may provide a useful treatment alternative for patients with treatment-resistant depression.

The effect of desipramine on body weight in depression.

Twenty-six patients with major depressive disorder were treated with desipramine for 4 weeks to determine the effect of the drug on body weight. Responders to desipramine showed a weight gain only at Weeks 3 and 4; nonresponders had a nonsignificant loss of weight. The increase in body weight of the responders was independent of dosage, sex, and hospitalization status. These findings suggest that the small increase in body weight that occurs in patients taking desipramine is associated with treatment response. In addition, desipramine may be a valuable treatment alternative for those patients in whom excessive weight gain is undesirable.

T3 augmentation of antidepressant treatment in T4-replaced thyroid patients.

BACKGROUND: Clinicians may not consider using the thyroid hormone liothyronine sodium (levorotary isomer of triiodothyronine [T3]) for augmentation of antidepressant drugs in depressed patients who are also receiving the precursor hormone levothyroxine (levorotary isomer of thyroxine [T4]) for thyroid disease. We now report on the successful use of T3 augmentation therapy in seven of nine depressed patients who were also receiving T4 for thyroid disease. METHOD: Following an earlier single case report, we prescribed T3 augmentation therapy for eight depressed patients who had not responded to an adequate antidepressant drug trial and who were receiving T4 therapy for thyroid disease. T3 was prescribed in open-label fashion, and response was judged by the clinician, whose assessment was supplemented by the use of standardized rating scales. RESULTS: Seven of the nine patients were judged to respond to T3 augmentation. CONCLUSION: These results are consistent with a report of differential effects for T3 versus T4 augmentation in depressed patients free of thyroid disease. The results have implications for the treatment of depression in the presence of thyroid disease and for the mechanism of thyroid hormone potentiation of antidepressants.

Augmentation strategies: focus on anxiolytics.

Approximately 20% to 40% of patients will fail to respond to the first antidepressant used for their current major depressive episode. Furthermore, it has been suggested that a further 20% to 30% of patients will have only a partial response. There are four main options to consider in the treatment of these patients: optimization, substitution, augmentation, and combination therapy. Several combination antidepressant treatments have been used in treatment-refractory depression. Moreover, various augmentation strategies have also proved to be successful. Although the empirical data to support these treatment options are limited, augmentation treatment has several potential advantages over the other clinical options available, particularly substitution. These data are reviewed and clinical applications discussed. Particular attention is paid to the role of anxiolytics as augmentation agents in the treatment of major depression.

Do depressed subjects who have failed both fluoxetine and a tricyclic antidepressant respond to the combination?

BACKGROUND: Recent evidence suggests that the combination of fluoxetine and desipramine may provide a rapid and effective treatment for depression. METHOD: The current study evaluated 13 subjects with DSM-III-R nonpsychotic major depression who had previously failed either desipramine or imipramine and who were currently unsuccessfully treated with fluoxetine. Desipramine or imipramine was added to fluoxetine and Hamilton Rating Scale for Depression (HAM-D) scores, Beck Depression Inventory (BDI) scores, and plasma tricyclic levels were monitored for 3 weeks. RESULTS: Of the 13 subjects, 7 (54%) had a greater than 40% decline in HAM-D scores and 4 of these (31%) had 50% or greater decline in HAM-D. At week 3, responders (767 +/- 282 nmol/L) had a significantly higher mean tricyclic level as compared with nonresponders (515 +/- 95 nmol/L, F = 25.1, p < .0001), and change in BDI scores was significantly correlated with tricyclic level (r = -0.60, p < .05). CONCLUSION: These findings suggest that in some subjects the positive clinical effect of combining fluoxetine and a tricyclic antidepressant may be related to the plasma levels of the tricyclic compound.

A controlled comparison of light box and head-mounted units in the treatment of seasonal depression.

BACKGROUND: Patterns of response to the light box and head-mounted unit (HMUs) in seasonal affective disorder (SAD) appear to differ. The current study employed a "no light" condition to compare the response rates with the light box and HMU against a plausible placebo. METHOD: Forty-three subjects with DSM-III-R nonpsychotic, unipolar major depression, seasonal subtype, were randomly assigned, in a double-blind manner, to receive 2 weeks of active treatment with a light box (N=9) or HMU (N=12) that emitted no visible light, or 2 weeks of placebo treatment with a light box (N=12) or HMU (N=10) that emitted no visible light. Response was defined as a 50% or greater reduction in both the 17-item "typical" score and 8-item "atypical" score on the Structured Interview Guide for the Hamilton Rating Scale for Depression-SAD version (SIGH-SAD). RESULTS: Using ANOVA for repeated measures, with change in total SIGH-SAD score as the dependent measure, we found no significant main effect of light (F=0.20, p=N.S.) or unit (F=0.50, p=N.S.), and no interaction (F=0.21, p=N.S.). Using log-linear analysis, we found no significant difference in response rate between the four cells (likelihood ratio chi-square = 2.1, p=N.S.). Using chi-square analysis, we found no significant difference in response rates between patients who received light (48%) versus patients who received no light (41%; chi-square = 0.2, p=N.S.) or between patients who received the light box (38%) versus HMU (50%; chi-square = 0.62, p=N.S.). CONCLUSION: The failure to detect any significant difference in efficacy between active and placebo treatments calls into question the specificity of light in light therapy for SAD. Methodological limitations, particularly small sample size, are discussed.

Response to an open trial of a second SSRI in major depression.

BACKGROUND: We evaluated the efficacy of a second serotonin selective reuptake inhibitor (SSRI) in patients who had failed to respond to the first SSRI used. METHOD: Fifty-five patients with major depression who had failed one of the SSRIs for their current depressive episode were included. After failing a trial of one SSRI, they received a second SSRI in an open clinical trial. RESULTS: On the basis of the Clinical Global Impression-Improvement scale, 28 of 55 patients had a marked or complete antidepressant response. CONCLUSION: These data provide preliminary clinical evidence that substituting a second SRI may be a useful clinical alternative in depressed patients who fail to respond to an adequate trial of an SSRI.

The prevalence of cyclothymia in borderline personality disorder.

Sixty patients with personality disorders were evaluated by several different diagnostic instruments to determine the prevalence of cyclothymia in borderline personality disorder (BPD) and in other personality disorders (OPD). Cyclothymia occurred more frequently in BPD than in OPD, regardless of which diagnostic system was used. In contrast, the prevalence of major, minor, and intermittent depression, hypomania, and bipolar disorder was not significantly different in BPD as compared with OPD. Cyclothymic borderlines and noncyclothymic borderlines could not be distinguished on behavioral or functional measures. These results have implications for the diagnostic validity of both BPD and cyclothymia.

Seasonal variation of peripheral thyroid hormone levels in major depression.

The seasonal variation in thyroid function tests was examined in 138 patients with major depression. No alterations in thyroxine, free thyroxine index, triiodothyronine, T3 resin uptake and thyrotropin were observed across the four seasons. This applied to both male and female subgroups. These data suggest that seasonality does not account for the wide variability in abnormalities of thyroid function reported in depression.

Relationship between antidepressant partial and nonresponse and subsequent response to antidepressant augmentation.

OBJECTIVE: To evaluate the relationship between the degree of antidepressant nonresponse and subsequent response to lithium and triiodothyronine (T3) augmentation. METHOD: This is a retrospective analysis of data combined from two previous controlled studies of lithium and triiodothyronine augmentation of tricyclic antidepressants. RESULTS: There was no difference in the rate of augmentation response between partial and nonresponders to tricyclic antidepressant treatment. CONCLUSIONS: Augmentation response does not appear to be related to the degree of nonresponse to the preceding antidepressant trial.

Mexiletine in treatment-resistant bipolar disorder.

BACKGROUND: The purpose of this study was to evaluate the efficacy and safety of mexiletine, a medication with antiarrhythmic, anticonvulsant and analgesic properties, in treatment-resistant bipolar disorder patients. METHODS: Twenty subjects with rapid-cycling bipolar disorder who had failed to respond or were intolerant to lithium, valproic acid and carbamazepine were entered into the 6-week, open label study. Subjects were followed on a weekly basis for dosing of mexiletine, blood levels, and completion of the Hamilton Depression Rating Scale (HAM-D) and the Manic State Rating Scale (MSRS). "Burden of Mood Symptoms" (BMS) was calculated by combining scores for the HAM-D and MSRS. RESULTS: Thirteen subjects (10 female, 3 male), mean age 41 years (S.D.=7.6), and mean duration of illness 20 years (S.D.=7.7) completed the study. The dose range of mexiletine was 200-1200 mg/day. Full response (>/=50% reduction in BMS) was seen in 46% of the subjects, and a partial response (25-49% reduction in BMS) in 15%. Of note, 5/5 subjects with a mixed or manic state demonstrated a full or partial response. LIMITATIONS: This study has an open label design, and a small number of subjects. CONCLUSIONS: Mexiletine may be effective and safe in patients with highly treatment-resistant, chronic bipolar disorder. Randomized, controlled trials are required to confirm the current results.